Mitochondrial protein sorting as a therapeutic target for ATP synthase disorders
18.12.2014
Aiyar RS, Bohnert M, Duvezin-Caubet S, Voisset C, Gagneur J, Fritsch ES, Couplan E, von der Malsburg K, Funaya C, Soubigou F, Courtin F, Suresh S, Kucharczyk R, Evrard J, Antony C, St Onge RP, Blondel M, di Rago JP, van der Laan M, Steinmetz LM.
Nat Commun. 2014;5:5585.
A systemic and prevalent class of human diseases caused by mitochondrial dysfunction is termed mitochondriopathies. Despite our increasing knowledge on the underlying pathophysiological mechanisms, there are hardly any effective treatments for these diseases known to date. Therefore, the identification of molecular intervention points that can be therapeutically targeted to successfully treat mitochondriopathies is a major challenge in biomedical research. In this study we have used a yeast model of mitochondrial ATP synthase disorders to screen a drug repurposing library and to identify putative targets of active compounds by a chemical genomics approach. We found that both pharmacological and genetic modulations of the sorting of nuclear-encoded proteins into mitochondria by the TIM23 complex of the inner mitochondrial, have therapeutic effects in yeast as well as in patient-derived cells that show similar ATP synthase deficiency phenotypes. Our study establishes mitochondrial protein sorting as a potential intervention point for ATP synthase disorders. Due to the crucial role of this pathway in mitochondrial biogenesis, it may hold general value for the treatment of mitochondriopathies.
